Despite the fact that there have been significant developments in anti-cancer technology, such as radiotherapy, chemotherapy and hormone therapy, cancer still remains the second leading cause of death following heart disease in the United States. Most often, cancer is treated with chemotherapy utilizing highly potent drugs, such as mitomycin, paclitaxel and camptothecin. In many cases, these chemotherapeutic agents show a dose responsive effect, and cell killing is proportional to drug dose. A highly aggressive style of dosing is thus necessary to eradicate neoplasms. However, high-dose chemotherapy is hindered by poor selectivity for cancer cells and severe toxicity to normal cells. This lack of tumor-specific treatment is one of the many hurdles that needs to be overcome by current chemotherapy.
One solution to current chemotherapy limitations would be to deliver a biologically effective concentration of anti-cancer agents to the tumor tissues with very high specificity. To reach this goal, much effort has been undertaken to develop tumor-selective drugs by conjugating anti-cancer drugs to such ligands as hormones, antibodies, or vitamins. For example, the low molecular weight vitamin compound, folate, is useful as a tumor-targeting agent.
Another approach to overcoming current chemotherapeutic limitations would be to deliver a combination of a tumor-targeted drug with one or more chemotherapeutic agents where the toxicity profile of the tumor-targeted drug and the chemotherapeutic agent are different. A further modification of this approach is to use the tumor-targeted drug and the chemotherapeutic agent in the combination treatment in amounts of each lower than typically used when the tumor-targeted drug or the chemotherapeutic agent is used alone for treatment.
Folate is a member of the B family of vitamins and plays an essential role in cell survival by participating in the biosynthesis of nucleic acids and amino acids. This essential vitamin is also a high affinity ligand that enhances the specificity of conjugated anti-cancer drugs by targeting folate receptor (FR)-positive cancer cells. The FR, a tumor associated glycosylphosphatidylinositol anchored protein, can actively internalize bound folates and folate conjugated compounds via receptor-mediated endocytosis. It has been found that the FR is up-regulated in more than 90% of non-mucinous ovarian carcinomas. The FR is also found at high to moderate levels in kidney, brain, lung, and breast carcinomas while it occurs at low levels in most normal tissues. The FR density also appears to increase as the stage of the cancer becomes more advanced.
Folate-targeted drugs have been developed and are being tested in clinical trials as cancer therapeutics. EC145 comprises a highly potent vinca alkaloid cytotoxic chemotherapeutic agent, desacetylvinblastine hydrazide (DAVLBH), conjugated to folate. The EC145 molecule targets the folate receptor found at high levels on the surface of epithelial tumors, including non-small cell lung carcinomas (NSCLC), ovarian, endometrial and renal cancers, and others, including fallopian tube and primary peritoneal carcinoma. Without being bound by theory, it is believed that EC145 binds to tumors that express the folate receptor delivering the vinca moiety directly to cancer cells while avoiding normal tissue. Upon binding, EC145 enters the cancer cell via endocytosis, releases DAVLBH and causes cell death by inhibiting formation of the mitotic assembly required for cell division. EC145 has the Chemical Abstracts Registry Number 742092-03-1 and the following formula
As used herein, in the context of a method of treatment, a use, a composition, a pharmaceutical composition, a kit, or a combination, the term EC145 means the chemotherapeutic agent, as indicated above, or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent may be present in solution or suspension in an ionized form, including a protonated form. EC145 can be synthesized, for example, by the method described in PCT/US11/037,134, incorporated herein by reference. EC145 is used interchangeably with the term “conjugate” herein.
In one embodiment, a method of treatment of a cancer is provided. The method comprises administering EC145 in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, apoptosis induction, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
In another embodiment, the preceding method wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin (e.g., PLATINOLT™), carboplatin (e.g., PARAPLATIN™), topotecan (e.g., HYCAMTIN™), irinotecan (e.g., CAMTOSAR™), bevacizumab (e.g., AVASTIN™), erlotinib (e.g., TARCEVA™), lapatinib (e.g., TYKERB™), and pemetrexed (e.g., ALIMTA™) is described.
In another embodiment, use of EC145 in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, apoptosis induction, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition for the treatment of folate receptor expressing cancer cells is described.
In another embodiment, the use described above is provided wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
In another embodiment, the use is provided of EC145 for the manufacture of a medicament for the treatment of folate receptor expressing cancer cells in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, apoptosis induction, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
In another embodiment, the use for manufacture of a medicament described above wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed is described.
In another embodiment, a pharmaceutical composition or combination comprising EC145 and one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, apoptosis induction, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
In another embodiment, the pharmaceutical composition or combination described in the preceding embodiment wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed is described.
In another embodiment, a composition comprising EC145 and one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, apoptosis induction, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
In another embodiment, the composition described in the preceding embodiment wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed is described.
In any of the above-described embodiments, the chemotherapeutic agent can also be doxorubicin, or a modified form of doxorubicin such as pegylated doxorubicin (e.g., DOXIL™). The doxorubicin (e.g., DOXIL™) can be liposome-encapsulated.
Several embodiments of the invention are described by the following enumerated clauses:
1. A method of treatment of a cancer, the method comprising the step of administering EC145 in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
2. The method of clause 1 wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
3. The method of clause 1 or 2 wherein the chemotherapeutic agent is carboplatin.
4. The method of clause 1 or 2 wherein the chemotherapeutic agent is bevacizumab.
5. Use of EC145 in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition for the treatment of folate receptor expressing cancer cells.
6. The use of clause 5 wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
7. The use of clause 5 or 6 wherein the chemotherapeutic agent is carboplatin.
8. The use of clause 5 or 6 wherein the chemotherapeutic agent is bevacizumab.
9. Use of EC145 for the manufacture of a medicament for the treatment of folate receptor expressing cancer cells in combination with one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
10. The use of clause 9 wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
11. The use of clause 9 or 10 wherein the chemotherapeutic agent is carboplatin.
12. The use of clause 9 or 10 wherein the chemotherapeutic agent is bevacizumab.
13. The method or use of any one of the preceding clauses wherein the folate receptor expressing cells are epithelial tumor cells.
14. The method or use of clause 13 wherein the epithelial tumor is an ovarian, an endometrial or a non-small cell lung tumor.
15. The method or use of any one of clauses 13 to 14 wherein the folate receptor expressing epithelial tumor is an ovarian tumor.
16. The method or use of any one of clauses 13 to 15 wherein the tumor is a primary tumor.
17. The method or use of any one of clauses 13 to 15 wherein the tumor is a metastatic tumor.
18. The method or use of any one of the preceding clauses wherein the chemotherapeutic agent is administered in a dose that is 50 to 80% of the maximum tolerated dose for the chemotherapeutic agent.
19. A pharmaceutical composition comprising EC145 and one or more chemotherapeutic agents having a mode of action selected from the group consisting of angio genesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
20. The composition of clause 19 wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
21. The composition of clause 19 to 20 wherein the chemotherapeutic agent is carboplatin.
22. The composition of clause 19 to 20 wherein the chemotherapeutic agent is bevacizumab.
23. A composition comprising EC145 and one or more chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition for treating a cancer.
24. The composition of clause 23 wherein the one or more chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
25. The composition of clause 23 or 24 wherein the chemotherapeutic agent is carboplatin.
26. The composition of clause 23 or 24 wherein the chemotherapeutic agent is bevacizumab.
27. The composition, method, or use of any one of the preceding clauses wherein the EC145 or the chemotherapeutic agent is in a parenteral dosage form.
28. The composition, method, or use of any one of the preceding clauses wherein the dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
29. The composition, method, or use of any one of the preceding clauses wherein the EC145 or the chemotherapeutic agent is in a composition and wherein the composition further comprises a pharmaceutically acceptable carrier.
30. The composition, method or use of clause 29 wherein the pharmaceutically acceptable carrier is a liquid carrier.
31. The composition, method or use of clause 30 wherein the liquid carrier is selected from the group consisting of saline, glucose, alcohols, glycols, esters, amides, and a combination thereof.
32. The composition, method, or use of any one of the preceding clauses wherein the EC145 or the chemotherapeutic agent is administered in a therapeutically effective amount.
33. The composition, method, or use of clause 32 wherein the effective amount ranges from about 1 ng to about 1 mg per kilogram of body weight.
34. The composition, method, or use of clause 33 wherein the effective amount ranges from about 100 ng to about 500 μg per kilogram of body weight.
35. The composition, method, or use of clause 34 wherein the effective amount ranges from about 100 ng to about 50 μg per kilogram of body weight.
36. The composition, method, or use of any one of the preceding clauses wherein the tumor is a platinum-resistant ovarian tumor.
37. A method of treatment of a cancer, the method comprising the steps of                administering EC145 to a patient; and        administering to the patient one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.        
38. Use of EC145 in combination with one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition for the treatment of folate receptor expressing cancer cells.
39. Use of EC145 for the manufacture of a medicament for the treatment of folate receptor expressing cancer cells in combination with one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
40. The method or use of any one of clauses 37 to 39 wherein the additional chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
41. The method or use of any one of clauses 37 to 40 wherein the additional chemotherapeutic agent is selected from the group consisting of carboplatin and bevacizumab.
42. The method or use of any one of clauses 37 to 41 wherein the additional chemotherapeutic agent is carboplatin.
43. The method or use of any one of clauses 37 to 41 wherein the additional chemotherapeutic agent is bevacizumab.
44. The use of any one of clauses 38 to 43 wherein the folate receptor expressing cells are epithelial tumor cells.
45. The use of clause 44 wherein the epithelial tumor is an ovarian, an endometrial, or a non-small cell lung tumor.
46. The use of clause 45 wherein the folate receptor expressing epithelial tumor is an ovarian tumor.
47. The use of clause 45 wherein the folate receptor expressing epithelial tumor is a non-small cell lung tumor.
48. The method of any one of clauses 37 or 40 to 43 wherein the cancer is an epithelial cancer.
49. The method of clause 48 wherein the epithelial cancer is an ovarian, an endometrial, or a non-small cell lung cancer.
50. The method of clause 49 wherein the epithelial cancer is an ovarian cancer.
51. The method of clause 49 wherein the epithelial cancer is a non-small cell lung cancer.
52. The method or use of any one of clauses 37 to 51 wherein the cancer or the cancer cells comprise a primary tumor.
53. The method or use of any of one of clauses 37 to 51 wherein the cancer or the cancer cells comprise metastatic tumor cells.
54. The method or use of any one of clauses 37 to 53 wherein the additional chemotherapeutic agent is administered at a dose that is 50 to 80% of the maximum tolerated dose for the chemotherapeutic agent.
55. The method or use of any one of clauses 37 to 54 wherein the EC145 and the additional chemotherapeutic agent are in parenteral dosage forms.
56. The method or use of clause 55 wherein the dosage forms are independently selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
57. The method or use of any one of clauses 37 to 56 wherein the EC145 is in a composition and the additional chemotherapeutic agent is in a composition and wherein the compositions further comprise pharmaceutically acceptable carriers.
58. The method or use of clause 57 wherein the pharmaceutically acceptable carriers are liquid carriers.
59. The method or use of clause 58 wherein the liquid carriers are independently selected from the group consisting of saline, glucose, alcohols, glycols, esters, amides, and a combination thereof.
60. The method or use of any one of clauses 37 to 59 wherein the EC145 and the chemotherapeutic agent are administered in therapeutically effective amounts.
61. The method or use of clause 60 wherein the effective amounts range from about 1 μg/m2 to about 500 mg/m2 of body surface area.
62. The method or use of clause 61 wherein the effective amounts range from about 1 μg/m2 to about 300 mg/m2 of body surface area.
63. The method or use of clause 60 wherein the effective amounts range from about 10 μg/kg to about 100 μg/kg of patient body weight.
64. The method of clause 50 wherein the cancer is a platinum-resistant ovarian cancer.
65. The use of clause 46 wherein the tumor is a platinum-resistant ovarian tumor.
66. The method or use of any one of clauses 37 to 65 wherein the EC145 and the additional chemotherapeutic agent are in sterile containers or packages.
67. The method or use of any one of clauses 37 to 66 wherein the EC145 and the additional chemotherapeutic agent have a purity of at least 90% based on weight percentage.
68. The method or use of any one of clauses 37 to 67 wherein the EC145 is in the form of a reconstitutable lyophilizate.
69. The method or use of any one of clauses 37 to 68 wherein the EC145 and the additional chemotherapeutic agent are in sterile, pyrogen-free aqueous solutions.
70. A composition or combination comprising EC145 and one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
71. A composition or combination for treating a cancer comprising EC145 and one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
72. A kit comprising EC145 and one or more additional chemotherapeutic agents having a mode of action selected from the group consisting of angiogenesis inhibition, microtubule assembly inhibition, DNA cross-linking, topoisomerase inhibition, DNA intercalation, DNA synthesis inhibition, tyrosine kinase inhibition, and mitosis inhibition.
73. The composition, combination, or kit of any one of clauses 70 to 72 wherein the additional chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, topotecan, irinotecan, bevacizumab, erlotinib, lapatinib, and pemetrexed.
74. The composition, combination, or kit of any one of clauses 70 to 73 wherein the additional chemotherapeutic agent is selected from the group consisting of carboplatin and bevacizumab.
75. The composition, combination, or kit of any one of clauses 70 to 74 wherein the additional chemotherapeutic agent is carboplatin.
76. The composition, combination, or kit of any one of clauses 70 to 74 wherein the additional chemotherapeutic agent is bevacizumab.
77. The composition, combination, or kit of any one of clauses 70 to 76 wherein the EC145 and the additional chemotherapeutic agent are in parenteral dosage forms.
78. The composition, combination, or kit of clause 77 wherein the dosage forms are independently selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
79. The composition, combination, or kit of any one of clauses 70 to 78 wherein the EC145 and the additional chemotherapeutic agent are in pharmaceutical compositions and the compositions further comprise pharmaceutically acceptable carriers.
80. The composition, combination, or kit of clause 79 wherein the pharmaceutically acceptable carriers are liquid carriers.
81. The composition, combination, or kit of clause 80 wherein the liquid carriers are independently selected from the group consisting of saline, glucose, alcohols, glycols, esters, amides, and a combination thereof.
82. The composition, combination, or kit of any one of clauses 70 to 81 wherein the EC145 and the chemotherapeutic agent are in therapeutically effective amounts.
83. The composition, combination, or kit of any one of clauses 70 to 82 wherein the EC145 and the additional chemotherapeutic agent are in sterile containers or packages.
84. The composition, combination, or kit of any one of clauses 70 to 83 wherein the EC145 and the additional chemotherapeutic agent have a purity of at least 90% based on weight percentage.
85. The composition, combination, or kit of any one of clauses 70 to 83 wherein the EC145 and the additional chemotherapeutic agent have a purity of at least 95% based on weight percentage.
86. The composition, combination, or kit of any one of clauses 70 to 85 wherein the EC145 is in the form of a reconstitutable lyophilizate.
87. The composition, combination, or kit of any one of clauses 70 to 86 wherein the EC145 and the additional chemotherapeutic agent are in sterile, pyrogen-free aqueous solutions.
88. The method or use of any one of clauses 37 to 59 wherein the EC145 and/or the additional chemotherapeutic agent are administered at doses lower than their maximum tolerable doses.
89. The composition, combination, or kit of any one of clauses 70 to 85 or the method or use of any one of clauses 37 to 67 wherein the EC145 is in the form of a lyophilizate.